PROJECT SUMMARY Marked heterogeneity among individuals with autism spectrum disorder (ASD) is a significant problem facing the autism community. Heterogeneity makes it difficult to identify core biological disruptions. It also hampers the development and validation of targeted and consistently effective therapeutics. In particular, the lack of precise, psychometrically robust, change sensitive outcome measures for core symptomatology represents a key barrier for clinical trials and for detecting mechanisms underlying manifest symptoms. This project proposes to develop and validate an innovative new observer report measure for ASD that attempts to capture heterogeneity in core symptoms along positive and negative dimensions, akin to those that have been successful in quantifying heterogeneity and facilitating key biological and therapeutic discoveries in schizophrenia. Using state-of-the-art procedures put forth by the NIH Patient-Reported Outcome Measurement Information System (PROMIS) initiative, this project will develop, calibrate, and validate a new tool - the Positive and Negative Inventory for ASD (PNI) - for assessing core ASD symptoms with unprecedented precision of symptom description and discrimination, along conceptually novel dimensions. First, our preliminary item pool will be refined with key stakeholder input from caregivers and national experts. Next, caregivers of 1,000 3-11 year old children with ASD and 400 typically developing and non-ASD clinical controls will complete the PNI. A combination of classical item analysis and factor analysis will be used to identify the best-performing items, which will then be calibrated using Item Response Theory (IRT) and co-calibrated with legacy measures to demonstrate superiority of PNI item and scale function. Baseline inter-rater and 6-week test-retest reliability, 24-week change sensitivity, and sensitivity in the context of an upcoming clinical trial all will be assessed, both convergent and divergent validity will be tested, and a short form will be developed. Preliminary data demonstrate both the utility of parsing individual behaviors, currently subsumed within larger categories, into positive and negative dimensions and the success of PROMIS methods and IRT for developing sensitive tools for ASD. We anticipate that this innovative, scientifically rigorous study will result in a calibrated and validated assessment tool for ASD with an empirically-supported factor structure and items that are both precise in their descriptive capturing of symptoms and sensitive to variability in the latent dimensions, within and across children. We also expect that the PNI will show excellent reliability and change sensitivity, offering a promising outcome measure for use in ASD clinical trials. Long term, we expect this research to have significant clinical benefits, including: 1) offering a new tool for assessing experimental therapeutics, 2) providing a new framework within which to test brain mechanisms and genetic contributions to specific feature manifestations, and 3) contributing to more nuanced application of targeted treatment in community clinical practice by offering a rapid, innovative, precise, and sensitive way to quantify heterogeneity in ASD.